Interstitial pneumonia is an inflammation of lung stroma, which means an inflammation of alveolar wall and peripheral supporting tissue. While it includes local one and diffuse one, interstitial pneumonia generally means diffuse interstitial pneumonia, including acute type and chronic type. Histologically, it is classified into five types of UIP (usual or classical interstitial pneumonia), BIP (obstructive bronchiolar interstitial pneumonia), DIP (desquamative interstitial pneumonia), LIP (lymphoid interstitial pneumonia) and GIP (giant cell interstitial pneumonia). Those having an unknown cause are called idiopathic interstitial pneumonia (XIP) in Japan and idiopathic pulmonary fibrosis (IPF) in US and Europe. Those having a known cause include pneumoconiosis, hypersensitivity pneumonitis, radiation pneumonitis, infection disease and the like. The disease sometimes accompanies a systemic dusease, such as sarcoidosis, histiocytosis X, collagen disease and the like. Clinically, dry coughing, exertional dyspnea, fever, clubbing of finger, cyanosis and the like are observed. One associated with systemic disease shows other systemic symptoms. The disease shows Velcro rale (fine crackle) by chest auscultation, ground glass opacity in an early stage, then fine particle-like shadow, and orbicular shadow and honeycomb shadow as the disease progresses, by chest X-ray image. By ventilatory function test, restrictive ventilatory defect, diffusion disturbance and hypoxemia are observed. It is an intractable disease with poor prognosis that shows fibrosis or honey cone lung as the final image.
Pulmonary fibrosis in interstitial pneumonia is pathologically alveolar septal tylosis, mainly characterized by growth of type II alveolar epithelial cells and fibroblast, and an increase in the collagen fibers produced by fibroblast. Its etiology is not certain but involvement of various cytokines is postulated. That is, known cellular groups involved therein are fibroblast, smooth muscle cell, hematocyte-derived macrophage, lymphocyte, neutrophile, acidocyte and basocyte, all of which constituting the mesenchymal cell, and alveolar epithelial cell, respiratory epithelial cell, vascular endothelial cell and the like as epidermic cells. These cells are activated by inflammatory stimulaion and the like and express various cytokines and the like, and induce changes in adhesion molecules. By these, pulmonary tissues are damaged, which triggers proliferation of type II alveolar epithelial cell and fibroblast, thereby advancing fibrosis.
Pulmonary fibrosis is a disease where diffuse fibroplasia of alveolar wall is observed, and is mainly characterized by dry coughing and exertional dyspnea. The name of pulmonary fibrosis means the end of interstitial pneumonia in a narrow sense, but in a wide sense, it means concomitant presence of pulmonary fibrosis in a narrow sense and interstitial pneumonia. Any interstitial pneumonia can cause this disease. It shows noticeable diffuse honeycomb shadow and pulmonary atrophy by X-ray chest image, and restrictive ventilatory defect, diffusion disturbance and hypoxemia are found by a ventilatory function test.
On the other hand, an antitumor agent, bleomycin, is known to cause, as a side effect, diffuse alveolar damage in the acute stage, and interstitial pneumonia and pulmonary fibrosis in the chronic stage. In an animal test, too, the administration of bleomycin shows initial images of interstitial pneumonia in the acute stage, and tylosis of alveolar wall, growth of type II alveolar cells and fibroblasts in the chronic stage, and many studies have been made as a model of human interstitial pneumonia and pulmonary fibrosis.
The conventional main therapy of such interstitial pneumonia and pulmonary fibrosis is administration of a steroid drug against active symptoms. This agent does not bring about a cure of the disease, but suppression of activity of the disease and stabilization of disease state. Thus, the utility of the drug is open to question. Moreover, a weight loss due to the steroid drug administration frequently induces acute exacerbation, which, in rare instances, is known to result in a death, and administration of a steroid drug is considered to be ineffective particularly in chronic cases. In the case of sarcoidosis, it is considered to even aggravate the long term prognosis.
Therefore, the creation of a drug aiming at a cure of the disease itself of the above-mentioned interstitial pneumonia, pulmonary fibrosis and the like has been awaited.
As a compound having a Rho kinase inhibitory activity, a compound of the formula (I) to be mentioned later has been reported (WO98/06433). Certain isoquinolinesulfonamide derivative and isoquinoline derivative are also reported to show a Rho kinase inhibitory activity (WO98/06433 and Naunyn-Schmiedeberg's Archives of Pharmacology 385(1) Suppl., R219, 1998).
The pharmaceutical use of a compound having a Rho kinase inhibitory activity is disclosed in WO98/06433, and described to be widely useful as a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a cerebrovascular spasm suppressant, a therapeutic agent of asthma, a therapeutic agent of peripheral circulatory disturbance, a premature delivery preventive, a therapeutic agent of arterial sclerosis, an anticancer drug, an anti-inflammatory agent, an immunosuppressant, a therapeutic agent of autoimmune diseases, an anti-AIDS agent, a therapeutic agent of osteoporosis, a therapeutic agent of retinopathy, a cerebral function improver, a contraceptive drug, and a gastrointestinal tract infection preventive. On the other hand, WO98/06433 does not teach its usefulness for the prevention and treatment of interstitial pneumonia and pulmonary fibrosis, or a description to suggest such effect.
Furthermore, the compound of formula (I) has been already known to be useful as an agent for the prophylaxis and treatment of disorders of circulatory organs such as coronary, cerebral, renal, peripheral artery and the like (e.g., a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent of renal and peripheral circulation disorder, a suppressive agent of cerebrovascular contraction and the like), which is potent and long lasting, and also as a therapeutic agent of asthma (JP-A-62-89679, JP-A-3-218356, JPA-4-273821, JP-A-5-194401, JP-A-6-41080 and WO95/28387).
The isoquinolinesulfonamide derivative described in the above-mentioned WO98/06433 is known to be effective as a vasodilating agent, a therapeutic agent of hypertension, a cerebral function improver, an anti-asthma agent, a heart protecting agent, a platelet aggregation inhibitor, a therapeutic agent of neurologic manifestation, an anti-inflammatory agent, an agent for the prevention and treatment of hyperviscosity syndrome, a therapeutic agent of glaucoma, a diminished tension agent, a motor paralysis improver of cerebral thorbmbosis, an agent for prevention and treatment of virus infection and transcriptional control factor inhibitor (JP-A-57-200366, JP-A-61-227581, JP-A-2-256617, JP-A-4-264030, JP-A-6-56668, JP-A-6-80569, JP-A-6-293643, JP-A-7-41424, JP-A-7-277979, WO97/23222, JP-A-9-227381, JP-A-10-45598 and JP-A-10-87491).
Moreover, the isoquinoline derivative described in the above-mentioned publication (Naunyn-Schmiedeberg's Archives of Pharmacology 385(1) Suppl., R219, 1998) is known to be useful as an agent for the prevention and treatment of brain tissue disorder due to vasospasm (WO97/28130).
However, these compounds having Rho kinase inhibitory activity are not disclosed to be useful for prophylaxis and treatment of interstitial pneumonia and pulmonary fibrosis, and there is no description suggestive of such usefulness.